A significant fraction of breast cancers overexpress the ErbB2 receptor, which specifies poorer outcome but also provides an opportunity for targeted therapy. The mainstay of current breast cancer treatment are chemotherapeutic agents with substantial toxicity to normal tissues. Specifically targeting tumor cells would allow concentration of cytotoxic drugs in the tumor while reducing their side effects. We wish to generate ErbB2 receptor-targeted nanostructures to carry cytotoxic drugs, and test their efficacy as selective drug delivery vehicles against breast cancer cells in vitro and in an in vivo animal model. Our proposed work is a collaboration between two teams, one specializing in the fields of nanoscience and nanotechnology, selfassembly, organic chemistry, and polymer chemistry (Stupp [PI];Scheidt;Nguyen, and O'Halloran), and another in cancer biology (H. Band and V. Band). Three platforms will be designed to target breast cancer cells: cylindrical supramolecular nanofibers, copolymer spherical micelles, and nanostructure-loaded liposome. The first project will develop multifunctional, self-assembling nanofibers that carry chemotherapy agents in their interior and a high density of external signals designed to bind to ErbB2 positive cells, along with magnetic resonance imaging agents for in vivo detection. The therapeutic compounds to be incorporated include doxorubicin, cyclophosphamide and taxotere;all proven treatments for cancer, but with significant detrimental side effects. The second system will be self-assembling block copolymer micelles, synthesized using living olefin metathesis polymerization. The nanostructure-forming copolymers will have chemotherapy agents in their hydrophobic segments and the antibodies to ErbB2 covalently bound to their external hydrophilic segments. The third system will be a liposome armed with antibody, encapsulating within it bundles of the multifunctional nanofibers. We will assess the nanostructure in vitro to establish if they inhibit growth and induce apoptosis of ErbB2 overexpressing breast cancer cell lines. Using in vivo mouse models we will determine the ability of the targeted therapeutic nanostructures to selectively localize to and inhibit the growth of implanted, ErbB2-positive nude mouse tumors. While the partnership focuses on breast cancer, our strategy would have broad applicability to other cancer therapies.